The central nervous system symptoms, such as cognitive, motor and behavioral dysfunctions, in the patients with AIDS are termed the AIDS dementia complex (ADC). However the mechanisms of the onset and progression of ADC are not well understood. Any agent that induces or potentiates HIV replication and/or the neurotoxicity of the HIV envelope protein gp120 may hasten the onset and progression of the disease. Exogenous opiates (e.g. morphine), which stimulate HIV replication in latently infected macrophages, are major risk factors for AIDS in the drug-abusing population. We hypothesized that opioid peptides, the naturally occurring opioids, serve as endogeous factors that modulate HIV replication and/or gp 120-related neurotoxicity and contribute further to the pathogenesis of ADC. As glial cells have been required for gp120-related neurotoxicity, we examined the effects of gp120 obtained from HIV-1 111B and HIV-1 SF2 on the production of cytokines and nitric oxide (NO) in unprimed or IFN-gamma primed mixed glial cell cultures. Mouse glial cells exposed to HIV-1SF2 gp120 increased the release of NO, TNF-alpha and IL-6. These effects of gp120 were significantly enhanced by priming glial cells with IFN-gamma. Tyrphostin A25, a tyrosine kinase inhibitor, inhibited HIV-1SF2 gp120-induced IL-6 production, indicating that tyrosine kinases are involved in the HIV-1SF2 gp120-induced signals. These results demonstrated that gp120 interacts with glial cells to release cytokines and/or NO, which may contribute to the neurotoxicity of gp120. The effects of opioid peptides on the gp120-modulated NO and cytokine production and the transactivation of HIV promoter will be studied. With a better understanding of the effects and mechanism(s) of endogenous opioid peptide, some rational strategies, such as using opioid receptor antagonists, to prevent HIV replication or the gp120-related neurotoxicity could be developed.